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Copyright © 2012 by Modern Scientific Press Company, Florida, USA
International Journal of Modern Biology and Medicine, 2012, 1(1): 48-81
International Journal of Modern Biology and Medicine
Journal homepage: www.ModernScientificPress.com/Journals/IJBioMed.aspx
ISSN: 2165-0136 Florida, USA
Review
Bioactivities of Berberine: An Update
Ren-You Gan*
School of Biological Sciences, The University of Hong Kong, Pokfulam Road, Hong Kong
* Author to whom correspondence should be addressed; E-Mail: kanrybiohk@hku.hk
Article history: Received 6 February 2011, Received in revised form 25 February 2012, Accepted 27
February 2012, Published 1 March 2012.
Abstract: Berberine has been used in traditional medicines. Recently, it has intrigued
increasing interest on its various significant bioactivities. In this review, the latest studies
on berberine were updated, including its natural sources, extraction and detection methods,
absorption and metabolism, and bioactivities. Furthermore, especial attention was paid to
its bioactivities, such as antioxidant, anti-microbial, anti-cancer, cardiovascular protective,
anti-diabetic, neuroprotective, anti-obesity, hepatoprotective, gastrointestinal protective,
anti-rheumatic, anti-angiogenic and anti-clastogenic effects, and potential mechanisms. The
accumulated evidence could provide theoretical basis for its future application in clinic to
prevent and treat diseases.
Keywords: berberine; separation; absorption; metabolism; bioactivities; mechanisms.
1. Introduction
Berberine (Fig. 1), a natural isoquinoline alkaloid with an intense yellow color and a bitter
taste, is found in many medicinal plants used in traditional Indian and Chinese medicine. Since it is
strongly yellow-colored, it is also used as a dye named “natural yellow 18”, being one of the yellow
dyes deriving from natural sources. In recent decades, berberine has intrigued increasing interest in its
significant bioactivities, such as antioxidant, anti-microbial and anti-cancer effects. This review mainly
provided latest information about the researches on berberine. Firstly, its natural sources were
introduced. Then, the extraction and detection methods were summarized. Next, its absorption and
metabolism were stated. Finally, its bioactivities were specially highlighted.
2. Natural Sources of Berberine
A number of medicinal plants, such as Coptidis rhizome and Barberry plants, are the major
natural sources of berberine. Researches found that berberine is mainly distributed in the roots, barks
and stems of plants. Coptidis rhizome (also named Coptis chinensis and Huanglian) is a famous herb
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49
used in traditional Chinese medicine for centuries to clear heat, dry dampness, purge fire and eliminate
toxin, and its yellow roots contain a high content of berberine (Tang et al., 2009; Wu et al., 2010).
Barberry plants, including Berberis aristata, Berberis aquifolium, Berberis asiatica, Berberis croatica,
Berberis thunbergii and Berberis vulgaris, are shrubs mainly grown in Asia and Europe, especially in
India and Iran, and their roots, barks, leaves and fruits are often used as folk medicine (Andola et al.,
2010; Imanshahidi and Hosseinzadeh, 2008; Kosalec et al., 2009; Kulkarni and Dhir, 2010). Other
berberine-containing medicinal plants include Tinospora cordifolia fruits (Khan et al., 2011),
Hydrastis canadensis (Imanshahidi and Hosseinzadeh, 2008), and Coscinium fenestratum (Rojsanga et
al., 2006).
Figure 1. The chemical structure of berberine
3. Extraction and Detection of Berberine
3.1. Extraction Methods
Highly purified berberine is prerequisite to research its bioactivities. Therefore, the extraction
methods are important to get a purified berberine. Firstly, medicinal plants should be dried and
powdered in order to increase the extraction efficiency. Then, it was defatted with petroleum ether (60-
80 �), and the marc was dried and further extracted by methanol (Srinivasan et al., 2008), or it could
be directly extracted by water (Narasimhan and Nair, 2005) or some organic solvents, such as
acetonitrile solution (Brown and Roman, 2008) as well as methanol and 95% ethanol with 1,2-
propanediol-modified supercritical carbon dioxide (Liu et al., 2006). Finally, raw extracts could be
further separated and purified by many methods, such as high performance liquid chromatography
(HPLC).
3.2. Detection Methods
A variety of detection methods, such as chromatographic and spectroscopic methods, were used
to detect and analyze berberine.
Chromatography was the most commonly used method to determine berberine in various
samples. HPLC was reported to analyze berberine in medicinal plants (Kamal et al., 2011), tissues
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50
(Wang et al., 2005) and plasma (Liu et al., 2011; Srinivasan et al., 2008). A liquid chromatography-
electrospray ionization-mass spectrometry (LC-ESI-MS) method could also determine berberine in the
plasma (Hua et al., 2007; Liu et al., 2011). Another chromatography method, high-performance thin-
layer chromatography (HPTLC), was also reported to quantify berberine content in herbal extract and
pharmaceutical dosage form, with a rapid, accurate, and cost-effective characteristics (Ghosh et al.,
2010; Rout et al., 2008).
In addition, spectroscopic-based methods were often employed to detect berberine. A light-
emitting diode induced fluorescence microplate analyzer could detect berberine in pharmaceutical
preparation and medicinal herbs with high recoveries (> 95%) (Zhang et al., 2011). Another
spectrofluorimetric method, based on significant fluorescence enhancement by supramolecular
complex formation between berberine and chloride, was also used to determine berberine in tablets,
serum and urine samples with high sensitivity and selectivity (Dong et al., 2011). Using water-soluble
CdTe quantum dots as probes, a fluorescence quenching method could also be employed for berberine
determination (Cao et al., 2010). Selective and affinitive imprinted polymers, such as polymer AD-10,
cooperating with spectrophotometric analysis, was used to determine berberine from natural products,
and this method had good efficiency, specificity and selectivity (Chen et al., 2011). 1H-NMR
spectroscopy was reported to directly detect berberine contents in Coptidis rhizoma and the purities of
commercial reagents of protoberberine alkaloids (Hasada et al., 2011; Li et al., 2009). The near-
infrared (NIR) diffuse reflectance spectroscopy combined with the artificial neural network (ANN)
was also a rapid and accurate method to detect the content of Berberine in the processed Coptis (Zhang
et al., 2008). Resonance Rayleigh scattering spectrum (RRS) spectrum method was a highly sensitive,
simple and rapid method to detect trace amounts of berberine in pharmaceuticals and goldthread
extracts (Peng et al., 2005). Other methods, such as capillary electrophoresis coupled with end-column
electrochemiluminescence (ECL) detection, were applied to determine berberine in tablets and
medicinal plants, such as Rhizoma coptidis (Du and Wang, 2010).
4. Absorption and Metabolism of Berberine
4.1. Absorption of Berberine
Berberine is mainly absorbed in the intestinal tract. However, it has a poor absorption and a low
bioavailability. After administrated via the femoral vein and oral gavage, little berberine was absorpted
from rat gastrointestinal tract, and the absolute bioavailability of berberine in rats was reported to be
only 0.68% (Chen et al., 2011), which is comparable with the result of another research that the
absolute oral bioavailability of berberine in rats was merely 0.36% (Liu et al., 2010). The mechanisms
of the low absorption and bioavailability of berberine remain incompletely understood, however,
recent studies have proposed some interpretation. Firstly, the structure of berberine limited its
absorption. Berberine, as a hydrophilic compound determinted by its structure, was lipophobic and
hard to pass through the plasma membrane of intestinal cells (Chen et al., 2011). Secondly, the
intestinal first-pass elimination of berberine was extensive. After intragastric administration, only half
of berberine could be kept intact through the gastrointestinal tract, meanwhile another half was
disposed by the small intestine (Liu et al., 2010). Finally, ATP-binding cassette (ABC) transporters
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51
might directly efflux the absorbed berberine back into the intestinal lumen. It was reported that
berberine was the substrate of several ABC transporters, such as P-glycoprotein (P-gp, also named
multidrug resistance protein1 (MDR1)) and multidrug resistance-associated protein (MRP) (Maeng et
al., 2002; Shitan et al., 2007). In a cell model, the uptake of berberine depended on the cellular ATP
level and its accumulation was less in the cells expressing MDR1 or MRP1 (Shitan et al., 2007). And
the inhibitors of MDR1, but not MRP1 or MRP2, could increase the uptake of berberine in Coca-2
cells (Kulkarni and Dhir, 2010; Zhang et al., 2011). By and large, the low absorption and
bioavailability of berberine was with complex mechanisms.
Since berberine has many important bioactivities, to increase its absorption and bioavailability
may significantly enhance its beneficial effects. Recent years, several methods have already been
found to increase its absorption and bioavailability. Several compounds, such as chitosan, lysergol, D-
α-tocopheryl polyethylene glycol 1000 succinate (TPGS) and sodium caprate, were reported to
increase the absorption and bioavailability of berberine in animal models. Chitosan could increase
berberine absorption in a dose-dependent manner, probably by improving the paracellular pathway of
berberine in rat intestinal tract (Chen et al., 2012). Lysergol, an alkaloid of the ergoline family, could
enhance the oral bioavailability of berberine in rats through increasing its stability in rat plasma (Patil
et al., 2011). TPGS could enhance berberine absorption in rats, probably through inhibiting the action
of P-gp and decreasing the efflux of absorbed berberine into the intestinal lumen (Chen et al., 2011).
Sodium caprate could stimulate mucosal-to-serosal transport of berberine, therefore significantly
increase the absorption of berberine in the intestine and its concentration in the plasma, as well as
enhance its anti-diabetic effect (Lv et al., 2010). Nanoparticle carriers could also increase berberine
oral bioavailability. By preparing berberine nanoparticles, anhydrous reverse micelle (ARM) delivery
system could improve its oral bioavailability and anti-diabetic efficacy (Wang et al., 2011). Another
nanoparticle berberine carrier with a heparin shell could effectively control the release of berberine and
treat Helicobacter pylori infection (Chang et al., 2011). Likewise, some formulations could improve
the bioavailability of berberine. In rats, an oral microemulsion formulation of berberine with
pharmaceutically acceptable ingredients, such as oleic acid, Tween 80 and PEG400, could improve the
bioavailability of berberine compared to the berberine tablet suspensions (Gui et al., 2008). In healthy
male volunteers, Rhizoma coptidis granules combined with cinnamon granules could promote
berberine absorption, increase its plasma concentration and detention time (Huang et al., 2011).
Berberine has a wide range of distribution in vivo. Compared to other organs, I125-labeled
berberine was highly found in the gallbladder and gastrointestinal system (Li et al., 2005). It was also
able to cross the blood-brain barrier (BBB) and enter the brain, such as the thalamus (Wang et al.,
2005) and hippocampus (Wang et al., 2005), which indicated that berberine might have protective
effects on central nervous system.
4.2. Metabolism of Berberine
The intestine and liver are both involved in the metabolism of berberine in vivo. In the
intestine, intestinal bacteria was reported to be responsible for metabolizing berberine, and played an
important role in the enterohepatic circulation of its metabolites (Zuo et al., 2006). There were three
major berberine metabolites found in the rat intestine (Liu et al., 2010). Liver is known to metabolize
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52
different kinds of compounds, and it is also the major organ for berberine metabolism. Oxidative
demethylenation and the subsequent glucuronidation in liver were the major metabolic pathways of
berberine in rats (Liu et al., 2009). After metabolized in the liver, the metabolites of berberine were
mainly excreted in the urine through kidney, and small parts could be excreted through the
hepatobiliary tract into the intestinal tract (Li et al., 2005). Cytochromes P450 (CYPs), the major
phase-I enzymes, was thought to take part in the oxidative demethylenation of berberine in the liver,
and UGT1A1 and UGT2B1 were responsible for their subsequent glucuronidation (Liu et al., 2009).
The major metabolites of berberine in the plasma and liver were oxidative metabolites M1 (via
demethylation) and M2 (via demethylenation) and their corresponding glucuronides (Li et al., 2011;
Liu et al., 2009). However, berberine had much more metabolites in the feces and urines. A study
showed that eleven berberine metabolites were identified in the feces and urine of mice, including five
unconjugated metabolites mainly in the feces, and six glucuronide and sulfate conjugates
predominantly in the urine (Guo et al., 2011). Another study indicated that after oral administration of
berberine, seven metabolites (HM1-HM7) were found in the human urine, including
demethyleneberberine-2-O-sulfate (HM1), jatrorrhizine-3-O-β-D-glucuronide (HM2), thalifendine-10-
O-β-D-glucuronide (HM3), berberrubine-9-O-β-D-glucuronide (HM4), jatrorrhizine-3-O-sulfate
(HM5), 3,10-demethylpalmatine-10-O-sulfate (HM6) and columbamin-2-O-β-D-glucuronide (HM7),
as well as five metabolites (RM1-RM5) were identified from the rat urine, including
demethyleneberberine-2,3-di-O-β-D-glucuronide (RM1), berberrubine-9-O-β-D-glucuronide (RM2),
demethyleneberberine-2-O-sulfate (RM3), 3,10-demethylpalmatine-10-O-sulfate (RM4) and
thalifendine (RM5) (Qiu et al., 2008). Therefore, it is complicated for the metabolism of berberine in
vivo.
5. Bioactivities of Berberine
Berberine has been reported to have a range of bioactivities. These beneficial effects could be
helpful for the prevention and treatment of many diseases, such as cancer, cardiovascular diseases,
diabetes, neurodegenerative diseases, etc. The following part mainly summarized recent researches on
its bioactivities, as well as the potential mechanisms.
5.1. Antioxidant Effect of Berberine
Oxidative stress has been implicated in the pathophysiologic process of many chronic
inflammatory and degenerative diseases. The generation of reactive oxygen species (ROS) during
oxidative stress can damage DNA, protein and cells, and play an important role in the disease progress.
Natural antioxidants, such as polyphenols from medicinal plants, can quench ROS and strengthen the
endogenous antioxidant defence system, therefore often used to prevent and treat oxidative stress-
mediated diseases.
Berberine was reported to have high antioxidant ability (Shan et al., 2011). In vitro
experiments, it had significant reductive ability and radicals scavenging capacity. In a concentration
dependent manner, it could effectively scavenge 2, 2-azino bis (3-ethylbenzothiazoline-6-sulfonate)
(ABTS), 2, 2-diphenyl 1-picrylhydrazyl (DPPH) and nitric oxide radicals, and inhibit lipid
peroxidation (Shirwaikar et al., 2006). It could also protect cells from oxidative damage. In hydrogen
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53
peroxide (H2O2)-induced PC12 cell, it could decrease lactate dehydrogenase (LDH) release, ROS
content, and malondialdehyde (MDA) levels, thus inhibit cell apoptosis and increase cell viability (Xu
and Zhou, 2010). Similarly, 10-1000 µmol/L berberine could inhibit the damaging effects of H2O2 in
cultured rabbit corpus cavenosum smooth muscle cells (CCSMC) by increasing superoxide dismutase
(SOD) activity and decreasing LDH release and MDA content (Tan et al., 2007). In THP-1 monocyte-
derived macrophages, pre-treatment with berberine could inhibit NADPH oxidase-mediated
superoxide anon generation in a concentration (10-50 mmol/L) and time (6-24 h) dependent manner,
through selective inhibition of gp91 (phox) expression and enhancement of SOD activity (Sarna et al.,
2010). In crucian carp, it was reported to inhibit the activities of oxidase cytochrome P4501A
(CYP1A) and CYP3A, which could catalyze the oxidation of organic substances (Zhou et al., 2011). In
diabetic rats, it could significantly decrease MDA level while increase catalase, SOD, glutathione
peroxidase, and glutathione activities in liver tissue (Zhou and Zhou, 2011). Therefore, berberine may
be a good candidate for natural antioxidant.
5.2. Anti-microbial Effects of Berberine
Berberine has been used as an anti-microbial reagent for a long history because of its effects on
various microbes, such as virus, bacteria, fungi and protozoans. Table 1 lists recent studies on the anti-
microbial effect of berberine and its derivates.
The mechanisms of berberine-mediated anti-microbial effects remain incompletely understood.
However, several recent studies increased our knowledge in this area. Berberine could inhibit influenza
virus growth and infection in cells, probably by inhibiting virus protein trafficking/maturation and
inflammatory substances release-induced pathogenic changes (Cecil et al., 2011; Wu et al., 2011). Its
anti-HPV effect might be through inhibiting AP-1 and blocking viral oncoproteins E6 and E7
expression in cervical cancer infected with HPV (Mahata et al., 2011). Its anti-HIV effect might be
partly via suppressing RTase activity and inhibiting HIV protease inhibitor-induced inflammatory
response (Bodiwala et al., 2011; Zha et al., 2010). It could also inhibit herpes simplex virus (HSV),
probably through interfering with the viral replication cycle (Chin et al., 2010). Berberine-mediated
anti-bacterial effect was probably through inhibiting bacterial division protein FtsZ (Boberek et al.,
2010). In Escherichia coli, it could interact with FtsZ protein, and destabilize FtsZ protofilaments as
well as inhibit the FtsZ GTPase activity (Domadia et al., 2008). Berberine could inhibit Aspergillus
fumigates through the ergosterol biosynthesis pathway (Gao et al., 2011). In macrophages, berberine
chloride-mediated anti-leishmanial activity was through activating p38 MAPK along with inhibiting
ERK1/2 (Saha et al., 2011). Berberine chloride could also induce Leishmania donovani promastigote
apoptosis-like death accompanying with increased generation of reactive oxygen species (Saha et al.,
2009).
5.3. Anti-cancer Effect of Berberine
Recent years, berberine was reported to be a potential candidate for cancer treatment, because it
could effectively fight against a variety of cancer cells. Its anti-cancer effect was mainly attributed to
its actions on inducing cancer cell death, suppressing cancer cell growth and inhibiting cancer cell
metastasis. The following part focused on its different actions on cancer cells.
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5.3.1. Induction of cancer cell death
It was found that berberine could induce cell death in diverse cancer cells, such as breast
cancer, liver cancer and lung cancer. Apoptosis was the most common way involved in berberine-
induced cancer cell death in many cell lines and cancer cell xenograft (Choi et al., 2009). On the other
hand, autophagy and necrosis were also reported to be associated with berberine-induced cancer cell
death (Hou et al., 2011; Letasiova et al., 2006).
Table 1. Different Anti-Microbial Effects of Berberine
Anti-microbial effects Microbe References
Anti-viral effect H1N1 influenza A virus Cecil et al., 2011
Human cytomegalovirus Hayashi et al., 2007
Human immunodeficiency
virus (HIV)
Mahata et al., 2011; Zha et al., 2010
Human papillomaviruse Mahata et al., 2011
Herpes simplex virus (HSV) Chin et al., 2010
Anti-bacterial effect Aeromonas hydrophila Zhang et al., 2010
Bifidobacterium adolescentis Yan et al., 2009
Edwardsiella ictaluri Zhang et al., 2010
Escherichia coli Domadia et al., 2008; Zhang et al., 2010
Pseudomonas fluorescens Zhang et al., 2010
Staphylococcus aureus Kim and Son, 2005; Yu et al., 2005
Staphylococcus epidermidis Wang et al., 2009
Streptococcus agalactiae Zhang et al., 2010
Vibrio vulnificus Zhang et al., 2010
Anti-fungal effect Aspergillus fumigates Gao et al., 2011; Park et al., 2010
Candida Park et al., 2010; Wei et al., 2011
Cryptococcus neoformans Park et al., 2010
Anti-protozoal effect Leishmania Bahar et al., 2011; Saha et al., 2009 & 2011
Plasmodium Bahar et al., 2011
Trypanosome Bahar et al., 2011
Berberine could activate mitochondria and caspase-dependent apoptotic pathway in vitro (Patil
et al., 2010). In cultured cancer cell lines, it could induce the disruption of the mitochondrial
transmembrane potential, release of cytochrome c and apoptosis-inducing factor from the mitochondria
to the cytosol (Burgeiro et al., 2011; Ho et al., 2009; Wang et al., 2010). It could also up-regulate the
expression of pro-apoptotic Bax and Bak, activate ROS-mediated ER stress, and down-regulate the
expression of anti-apoptotic Bcl-2 and Bcl-xl (Chen et al., 2009; Eom et al., 2010; Katiyar et al., 2009;
Lin et al., 2006). Finally, a number of caspases, such as caspases 3, 4, 7, 8, and 9, could be activated by
berberine (Burgeiro et al., 2011; Yan et al., 2011). On the other hand, the death receptor pathway was
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55
activated in berberine-induced apoptosis (Lin et al., 2007). In human cervical carcinoma cells (HeLa),
berberine could increase the expression of Fas, FasL, TNF-α and TRAF-1, which could initiate cell
apoptosis, and subsequently activate caspase-3 and caspase-8 mediated cell apoptosis (Lu et al., 2010).
Besides, berberine could regulate caspase-independent cell death by inducing DNA strand break
through inhibition of topoisomerases and induction of DNA damage (Pinto-Garcia et al., 2010).
Many other apoptotic-related molecules were also reported to be involved in berberine-induced
cell apoptosis. Berberine could up-regulate the expression of p53 and p27, which play a pro-apoptotic
role in cancer cells (Lu et al., 2010; Patil et al., 2010). It could also induce the acetylation of α-tubulin
and this correlated with the induction of apoptosis (Khan et al., 2010). In HER2-overexpressing breast
cancer cells, it could promote cell apoptosis via down-regulating the HER2/PI3K/Akt signaling
pathway (Kuo et al., 2011). Similarly, in SK-MEL-2 cell line, inhibition of B-RAF/ERK survival
signaling pathway was involved in berberine-induced cell apoptosis (Burgeiro et al., 2011). In human
ductal breast epithelial tumor cell line (T47D cell line) and human erythro-myeloblastoid leukemia cell
line (K562 cell line), cyclooxygenase-2 (COX-2) and survivin, two anti-apoptotic proteins, could be
inhibited by berberine (Pazhang et al., 2011 & 2012). In human hepatoma carcinoma cell lines (HepG2
and SMMC7721 cell lines), it could induce cell apoptosis by downregulating CD147 (Hou et al.,
2011). In human renal cancer cell line (Caki cells), it could sensitize TRAIL-induced apoptosis
through down-regulating c-FLIP and Mcl-1 proteins and inducing the expression of GADD153, a
transcription factor involved in apoptosis (Lee et al., 2011; Lin et al., 2007). Berberine could also
inhibit the oncogentic H-Ras and c-fos in T24 bladder cancer cell line (Yan et al., 2011).
Meanwhile, berberine could induce cancer cell death via autophagy and necrosis. In human
hepatic carcinoma cell lines (HepG2 and MHCC97-L), berberine might induce autophagic cell death
with the mechanism of inducing Beclin-1 activation and mTOR inhibition by suppressing the activity
of Akt and up-regulating P38 MAPK signaling (Wang et al., 2010). In berberine-treated murine
melanoma B16 cell line, necrosis could be observed based on the damage of cell membrane integrity
(Letasiova et al., 2006).
5.3.2. Suppression of Cancer Cell Growth
It was reported that berberine could suppress the growth and proliferation of different cancer
cells. Cell cycle arrest was the main mechanism involved in berberine-induced suppression of cancer
cell growth in vitro. Berberine could induce cell cycle arrest at different cell cycle phases. It could
promote cell cycle arrest at G0/G1 checkpoint in different cancer cell lines, such as MCF-7 and MDA-
MB-231 breast cancer cell lines and human pulmonary giant cell carcinoma cell line (PG) (Kim et al.,
2010; Luo et al., 2008). Berberine-mediated G0/G1 cell cycle arrest might be partly via inhibiting the
expression of cyclin D1 (Luo et al., 2008). It could also induce G1-phase cell cycle arrest. For
example, In HER2-overexpressing breast cancer cells, BIU-87 and T24 bladder cancer cell lines, lung
tumor cells, osteosarcoma cells, human epidermoid carcinoma A431 cells, human glioblastoma T98G
cells and prostate cancer cell lines (DU145, PC-3 and LNCaP cells), it could induce G1-phase cell
cycle arrest (Eom et al., 2008; James et al., 2011; Kuo et al., 2011; Liu et al., 2009; Mantena et al.,
2006; Yan et al., 2011). Berberine-induced G1-phase cell cycle arrest might be dependent on p53 (Liu
et al., 2009), and regulated through increasing the expression of Cclk inhibitory proteins (Cdki), such
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56
as Cip1/p21 and Kip1/p27, inhibiting the expression of cyclin-dependent kinase (Cdk) 2, Cdk4, Cdk6
and cyclins D1, D2 and E, as well as enhancing the binding of Cdki to Cdk (Mantena et al., 2006a &
b). In addition, G1/S and G2/M phase cell cycle arrests were involved in berberine-induce cell cycle
arrest. In HL-60 cells, berberine caused cell accumulation in S-phase via a strong activation of Chk2,
phosphorylation and degradation of Cdc25A, and inhibition of Cdc2 (CDK1) and the proto-oncogene
cyclin D1 (Khan et al., 2010). In NCI-H838 cell line, berberine could suppress cell growth via
inducing G2/M arrest (Tungpradit et al., 2011). In human pancreatic cancer cells and human
pronzyelocytic leukemia HL-60 cells, it could simultaneously inhibit G1/S and G2/M cell cycle phases
by up-regulating the levels of Wee1 and down-regulating the levels of Cdc25c, CDK1 and cyclin B1
(Lin et al., 2006; Pinto-Garcia et al., 2010).
Except cell cycle arrest, berberine could suppress cell growth in other ways. In MCF-7 breast
cancer cells, berberine could inhibit cell growth partly via reducing side population (SP) cells and
ABCG2 expression (Kim et al., 2008). Besides, in Ehrlich ascites carcinoma cells, berberine could
inhibit cell proliferation by induction of DNA damage, inhibition of DNA and protein synthesis
(Letasiova et al., 2006).
Berbeirne also inhibited tumor growth in vivo. In both p53 expressing and p53 null lung tumor
xenografts, orally administration of berberine could inhibit the growth of tumor cells in vivo (James et
al., 2011; Katiyar et al., 2009). In a xenograft mouse model implanted with human tongue cancer SCC-
4 cells, treatment of berberine could reduce the tumor incidence and tumor size (Ho et al., 2009).
5.3.3. Inhibition of Cancer Cell Metastasis
Several important factors, such as ECM proteinases, play an important role in cancer cell
metastasis, and inhibition of these factors can suppress cancer cell migration and invasion. Recent
studies found that berberine could exert its anti-cancer effect partly by inhibiting cancer cell migration,
invasion and metastasis.
Berberine could inhibit two major ECM proteinases, matrix metalloproteinases (MMPs) and
urokinase-type plasminogen activator (u-PA), in cancer cell lines. In human hepatoma HepG2 cell line,
it could inhibit cell invasion through suppression of MMP-9 expression through PI3K-AKT and ERK
pathways (Liu et al., 2011). In human SCC-4 tongue squamous cancer cells, it could down-regulate u-
PA, MMP-2 and -9 expression via the FAK, IKK and NF-κB -mediated signaling pathways (Ho et al.,
2009). In MDA-MB-231 human breast cancer cells, it could suppress cell invasion by inhibiting TNF-
α-induced MMP-9 expression through down-regulation of AP-1 activity (Kim et al., 2008). In human
gastric cancer SNU-5 cells, it could prevent cell migration through inhibition of MMP-1, -2 and -9
gene expression (Lin et al., 2008). In human lung cancer cell line (A549 cells), it could inhibit cell
invasion via reducing MMP2 and u-PA expression (Peng et al., 2006). Inhibition of Rho GTPases was
also involved in berberine-mediated suppression of cancer cell migration. Berberine was reported to
suppress cancer cell migration by inhibiting the activation of RhoA, Cdc42 and Rac1 Rho GTPases
(Tsang et al., 2009). In a nasopharyngeal carcinoma cell line (5-8F), berberine could suppress Rho
GTPase activity and inhibit the phosphorylated Ezrin (phospho-Ezrin), which was highly expressed in
metastatic tumors, and then reduce the motility and invasion of cancer cells (Tang et al., 2009).
Besides, berberine could inhibit cancer cell migration through blocking the PKC-mediated signaling
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57
pathway (Lin et al., 2008), inhibit primary acute myeloid leukemia (AML) cells and leukemic stem
cells (LSCs) migration via down-regulating SDF-1 protein (Li et al., 2008), and suppress melanoma
cancer cell migration by inhibiting the expressions of COX-2, prostaglandin E (PGE)2 and PGE2
receptors (Singh et al., 2011).
In other ways, berberine could enhance the radiosensitivity of cancer cells (Liu et al., 2011;
Peng et al., 2008). In Hela cells transfected with connexin-32, it could potentize cell apoptosis induced
by X-rays irradiation, probably through the enhancement of gap junction intercellular communication
(GJIC) (Liu et al., 2011). Therefore, the anti-cancer effect of berberine is mainly involved in the
regulation of cancer cell growth, death and metastasis. In the future, it is necessary to verify its anti-
cancer effect from bench to bed.
5.4. Cardiovascular Protective Effect of Berberine
Many studies reported berberine could protect heart and vascular systems. On the one hand, it
could alleviate cardiotoxicity, improve cardiac dysfunction and arrhythmia. On the other hand, it was
able to fight against atherosclerosis due to its protective actions, such as inhibiting oxidative stress and
vascular inflammation, ameliorating endothelial dysfunction, suppressing vascular smooth muscle cell
(VSMC) proliferation and migration, and inhibiting foam cell formation and lipid accumulation.
5.4.1. Cardioprotective Effect
In vitro and in vivo studies, berberine was reported to have a potential protective role in heart.
In cultured neonatal rodent cardiomyocytes, it was found to be a muscarinic agonist at M2 receptors
and could reduce the contraction rate of cardiomyocytes (Salehi and Filtz, 2011). In a cardiotoxicity
mice model, berberine could attenuate the myocardial injury induced by doxorubicin (Zhao et al.,
2011). Similarly, it could improve LPS-induced cardiac dysfunction in rats (Yang et al., 2006). It was
also able to ameliorate cardiac dysfunction in hyperglycemic and hypercholesterolemic rats through
decreasing cardiac lipid accumulation and increasing glucose transport (Dong et al., 2011). In mice,
pre-treatment with berberine could significantly reduced LPS-induced cardiac dysfunction via
inhibiting myocardial apoptosis, cardiac I-κB α subnuit phosphorylation, and inflammatory factors
production, such as TNF-α, IL-1β and NO (Wang et al., 2011). Besides, in the rat type 2 diabetic
myocardial infarction model, berberine had an anti-arrhythmic effect, maybe via up-regulation of
IK1/Kir2.1 (Wang et al., 2011).
5.4.2. Anti-atherosclerosis Effect
Atherosclerosis is a complicated pathological condition in arteries. Many risk factors are found
to be associated with the pathophysiological process of atherosclerosis, such as oxidative stress and
vascular inflammation, endothelial dysfunction, VSMC proliferation and migration, foam cell
formation and lipid accumulation. Recently, increasing studies have found that berberine had multiply
protective effects against these vascular risk factors, and could be used to prevent and treat with
atherosclerosis.
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58
First, berberine could reduce vascular oxidative damage and inflammation. In macrophage, it
could significantly inhibit the expression of pro-inflammatory factors, such as TNF-α, and suppress
pro-inflammatory responses through AMPK and PPAR-γ activation (Chen et al., 2008; Jeong et al.,
2009). In human peripheral blood monocytes (PBMC), it could inhibit COX-2 expression via the
ERK1/2 signaling pathway (Guo et al., 2008). In apoE-knockout mice, chronic administration of
berberine could significantly ameliorate aortic lesions, inhibit oxidative stress and inflammatory
factors, such as adhesion molecules, in aorta (Wang et al., 2011). Second, it could improve endothelial
function. In both cultured endothelial cells and blood vessels isolated from rat aorta, berberine could
protect against endothelial injury and enhance the endothelium-dependent vasodilatation partly
through the activation of the AMPK pathway (Wang et al., 2009). It was also able to up-regulate and
mobilize circulating endothelial progenitor cells, as well as improve small artery elasticity in healthy
people (Xu et al., 2008 & 2009). Third, it could attenuate the proliferation and migration of VSMCs. In
a VSMC cell line (A7r5), berberine could inhibit cell proliferation through inducing cell cycle arrest
(Liu et al., 2011). It could also inhibit platelet-derived growth factor (PDGF)-induced VSMC growth
and migration via activation of AMPK/p53/p21 (Cip1) signaling and inhibition of Rac1 and Cdc42,
respectively (Liang et al., 2008). Fianlly, it could inhibit foam cell formation and promote cholesterol
efflux. In oxidized low-density lipoprotein (ox-LDL) pre-treated macrophage, berberine could
abrogate the formation of foam cells from macrophage, and reduce lipid accumulation in macrophage
via promoting LXRα-ABCA1-dependent cholesterol efflux (Lee et al., 2010). Another research found
berberine could inhibit the expression of nectin-like ox-LDL receptor-1 (LOX-1) and enhance the
expression of SR class B type I (SR-BI) in macrophage-derived foam cells (Guan et al., 2010), which
indicated that berberine might also promote cholesterol efflux via SR-BI. However, berberine was also
reported to promote in vivo foam cell formation and atherosclerosis development in apoE-knockout
mice (Li et al., 2009). This contradiction may be due to the different experimental models used and
further researches are needed to investigate its in vivo effect.
5.5. Anti-diabetic Effect of Berberine
There are two types of diabetes mellitus, in which type 1 diabetes is featured with islet damage
and lack of insulin, while type 2 diabetes is a chronic metabolic disease with the characteristics of
insulin resistance, hyperglycemia, hyperlipidemia, and severe complications, such as vascular and
nephritic injure. Berberine has recently been shown to have protective efficacy in both two type
diabetes because of its actions on the protection of islet cells and regulation of glucose, lipid and
insulin metabolism.
5.5.1. Improvement of Insulin Resistance
Insulin resistance plays a central role in the pathogenesis of type 2 diabetes. In the first place,
berberine could alleviate insulin resistance. In insulin-resistant muscle cells, berberine could overcome
insulin resistance, and the mechanisms involved in regulating insulin signaling pathway and reducing
PPARγ and FAT/CD36 expressions (Chen et al., 2009; Liu et al., 2010). In 3T3-L1 adipocytes,
berberine could reverse free-fatty-acid-induced insulin resistance through inhibiting IKKβ
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59
phosphorylation (Yi et al., 2008). In Diabetic Hamsters, Berberine could improve fat-induced visceral
white adipose tissue insulin resistance through increasing visceral white adipose tissue liver X
receptors (LXRs) and peroxisome proliferator-activated receptors (PPARs) expression, while
decreasing sterol regulatory element-binding proteins (SREBPs) expression (Li et al., 2011; Liu et al.,
2010). In high-fat-fed rats, berberine was able to improve insulin-resistant status at least partly via
AMPK activation (Lee et al., 2006). In the second place, it could increase insulin sensitivity and
secretion. Berberine could increase insulin secretion probably by increasing GLP-1 secretion, which is
an insulinotropic gut hormone released from intestinal L cells (Yu et al., 2010). In a rat pancreatic beta
cell line, it could increase glucose-stimulated insulin secretion (GSIS), probably as an agonist of fatty
acid receptor GPR40, which can enhance GSIS (Rayasam et al., 2010). In 3T3-L1 fibroblasts and
Min6 cells, it could act as an effective insulin sensitizing and insulinotropic agent through activation of
insulin/insulin-like growth factor-1 signaling cascade (Ko et al., 2005). In type 2 diabetic rats, it was
able to increase insulin sentivity, probably through protein kinase C-dependent up-regulation of insulin
receptor expression (Kong et al., 2009; Wang et al., 2011). In primary rat islets, berberine could also
enhance GSIS probably through up-regulating hepatic nuclear factor 4α (HNF4α) and glucokinase
(GK) activity (Wang et al., 2008).
5.5.2. Hypoglycemic Effect
High blood glucose is the main feature of diabetes, and can cause severe diabetic
complications. In vitro and in vivo studies, as well as clinical trials have found berberine could lower
hyperglycemia in diabetes. In alloxan-induced diabetic C57BL/6 mice, berberine could reduce blood
glucose by enhancing liver glycogen synthesis, and this action was mediated through the activation of
Akt signaling pathway (Xie et al., 2011). It could also enhance cell glucose uptake. In L929 fibroblast
cells, it was able to activate glucose uptake through its acute activation of the transport activity of
glucose transporter, GLUT1 (Cok et al., 2011). In 3T3-L1 adipocytes and L6 myocytes, it could
increase glucose uptake in an insulin-independent manner (Chen et al., 2010). Besides, berbreine could
improve glucose metabolism. In diabetic rats, it could lower fasting blood glucose through direct
inhibiting gluconeogenesis in liver, and this activity was not dependent on insulin activity, but as a
result of berberine-mediated mitochondria inhibition (Xia et al., 2011). Finally, berberine could inhibit
intestinal disaccharidase activity. In diabetic rats and normal rats, berberine was able to significantly
lower postprandial blood glucose level by suppressing intestinal disaccharidase and β-glucuronidase
activity, and this effect was partly dependent on the activation of PKA signaling pathway (Liu et al.,
2008 & 2010).
5.5.3. Hypolipidemic Effect
Hyperlipidemia is a potential risk factor for type 2 diabetes, and berberine was reported to
lower blood lipids, such as free fatty acids and cholersterol. In type 2 diabetic rats, it could
significantly lower blood lipids, such as low density lipoprotein-cholesterol (LDL-C) (Zhang et al.,
2008). In small clinical trials, berberine might play an important role in the treatment of type 2 diabetes
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60
via lowering blood free fatty acids, such as triglyceride, total cholesterol and LDL-C (Zhang et al.,
2008; Gu et al., 2010).
5.5.4. Amelioration of Diabetic Complications
Diabetes is accompanied with multiply complications, such as microvascular injure, diabetic
nephropathy and memory impairment. Berberine was reported to alleviate diabetic microendothelial
injury in vitro (Hao et al., 2011). Similarly, it could ameliorate endothelial dysfunction in diabetic rats
by enhancing NO bioavailability (Wang et al., 2009). It could also improve diabetes-induced renal
damage. In high glucose-induced rat glomerular mesangial cells, it was able to inhibit aldose reductase,
oxidative stress, as well as fibronectin and collagen accumulation (Liu et al., 2008 & 2009). In
streptozotocin-induced diabetic rats, could also alleviate rat renal injury by suppression of both
oxidative stress and aldose reductase (Liu et al., 2008). In diabetic C57BL/6 mice, it was able to
alleviate renal injury by reducing blood urea nitrogen, serum creatinine and 24-h albuminuria (Lan et
al., 2010). Besides, berberine could improve memory dysfunction in diabetic rats due to its protection
of cholinergic and antioxidant system (Bhutada et al., 2011).
5.5.5. Protection of Islets
The damage of islets is mainly involved in type 1 diabetes. Berberine was able to protect islet
cells from injure. In HIT-T15 pancreatic β cells, it could reduce palmitate-induced β cell lipoapoptosis
probably via up-regulating PPARγ expression (Gao et al., 2011). In nonobese diabetic mice, berberine
supplementation could significantly increase the number of decreased islets, and ameliorate insulin and
blood lipids status (Chueh and Lin, 2011). In type 1 diabetic mice, it could inhibit T cell-mediated
destruction of islet β cells and severe islet inflammation through suppressing Th17 and Th1
differentiation (Cui et al., 2009). In diabetic rats, it could also increase islet β cell regeneration,
antioxidant enzyme activity and decrease lipid peroxidation, therefore protect islets from oxidative
damage (Zhou et al., 2009).
5.6. Neuroprotective Effect of Berberine
It has been confirmed that berberine could enter into the central nervous system (Wang et al.,
2005), and it’s the prerequisite for its neuroprotective effect. Studies found it could fight against many
nervous system diseases, such as neurodegenerative diseases and neuronal injure. Berberine was
reported to combat against neurodegenerative diseases, especially Alzheimer’s disease (AD). AD is
featured with amyloid β (Aβ) aggregation, tau hyperphosphorylation and neuron death. Berberine
could fight against Aβ. In vitro experiments, berberine and its derivatives were found to inhibit Aβ
aggregation and the activity of acetylcholinesterase (AchE) (Habtemariam, 2011; Shan et al., 2011). In
cultured rat cortical neurons, it could inhibit Aβ-induced cell toxicity by increasing cell viability and
inhibiting cell apoptosis (Wang et al., 2011). It could also reduce Aβ secretion by modulating the
process of Aβ production (Asai et al., 2007). In addition, it was able to inhibit tau
hyperphosphorylation. In HEK293 cells transfected with tau, it could significantly reduce calyculin A-
induced tau hyperphosphorylation, probably through restoring protein phosphatase 2A activity and
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61
inhibiting glycogen synthase kinase-3β (GSK-3β) activation (Yu et al., 2011). Besides, in an AD rat
model, berberine chloride could ameliorate rat spatial memory impairment (Zhu and Qian, 2006).
Berberine also had a protective effect on different kinds of neuronal injure. It could alleviate toxic-
induced neuronal injure. In aluminum and ibotenic acid-induced rat neuronal damage models, it could
attenuate brain injury, improve the learning and memory ability impairment, inhibit neuron death and
promote neuron survival and differentiation (Lim et al., 2008; Zhang et al., 2009). It could also inhibit
neuro-inflammation. It could reduce the release of inflammatory factors and neurotoxic molecules
from activated microglia and inhibit neuro-inflammation response (Lu et al., 2010; Nam et al., 2010).
In experimental autoimmune encephalomyelitis (EAE) mice, it was able to effectively attenuate
clinical and pathological parameters of EAE, reduce the permeability of blood-brain barrier, decrease
the expression and activity of MMP-9, and inhibit the inflammatory infiltration (Ma et al., 2010). In
addition, it could protect brain from hypoxic and ischemic injury. In ischemic-induced mouse
organotypic hippocampal slice culture model, it could inhibit ischemic damage, at least partly
mediated by suppression of Bcl-2 phosphorylation (Cui et al., 2009). In ischemic-hypoxic-induced rat
pup brain, it could significantly reduce the brain injury and edema (Benaissa et al., 2009). Decreasing
the intracellular ROS level and subsequently inhibiting mitochondrial apoptotic pathway was reported
to be the main mechanism of berberine-mediated protection of ischemic brain injury (Zhou et al.,
2008).
Otherwise, berberine was able to inhibit ethanol withdrawal-induced hyperexcitability and
ethanol-induced rewarding effect in mice (Bhutada et al., 2010 & 2011). It could also inhibit morphine
and cocaine-induced locomotor sensitization through reducing dopamine biosynthesis, dopamine
receptor and N-methyl-D-aspartate (NMDA) receptor activities and post-synaptic neuronal activity
(Lee et al., 2009; Yoo et al., 2006).
5.7. Anti-obesity Effect of Berberine
It has been reported that berberine had an effect on obesity. It could inhibit adipogenesis. In
differentiating 3T3-L1 preadipocytes and mature adipocytes, it could inhibit adipogenesis, with the
mechanisms of inhibiting adipogenic enzymes, such as fatty acid synthase, acetyl-CoA carboxylase
and acyl-CoA synthase, SREBP-1, C/EBPα and PPARγ (Choi et al., 2006; Hu et al., 2010; Pham et al.,
2011). Similarly, in high-fat diet-induced obesity mice, it could reduce mouse food intake and weight,
probably through inhibiting the expression of PPARγ while increasing the expression of GATA-3 (Hu
and Davies, 2010). It could also inhibit pre-adipocyte differentiation. In mouse preadipocyte 3T3-L1, it
was able to inhibit pre-adipocyte differentiating into muture adipocyte by up-regulating both GATA
binding protein 2 and 3 (GATA-2 and GATA-3), while down-regulating PPARγ and α (Hu and
Davies, 2009; Huang et al., 2006). Besides, in obese mice, berberine treatment could significantly
lower both body and visceral adipose weights,probably through gut microbes-mediated decreasing
the degradation of dietary polysaccharides and lowering potential calorie intake (Xie et al., 2011).
5.8. Hepatoprotective Effect of Berberine
Berberine was reported to ameliorate nonalcoholic fatty liver disease (NAFLD). In NAFLD
rats, it could improve the recovery of hepatic steatosis and lipid metabolism disorder, and reduce
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62
inflammation and insulin resistance, with the mechanism of up-regulation of insulin receptor substrate-
2 (IRS-2) and down-regulation of uncoupling protein-2 (UCP2) (Xing et al., 2011; Yang et al., 2011).
Berberine might also be effective to alcoholic liver disease (ALD). In HepG2 cells, it could inhibit
acetaldehyde, the metabolic product of ethanol, induced production of pro-inflammatory factors, such
as IL-1β and TNF-α, probably through NF-κB signaling pathway (Hsiang et al., 2005). In addition,
berberine could inhibit liver fibrosis. In liver fibrosis rodent models, it could protect experimental liver
fibrosis through enhancing anti-oxidant system, inhibiting lipid peroxidation and hepatic stellate cell
proliferation (Sun et al., 2009; Zhang et al., 2008).
5.9. Gastrointestinal Protective Effect of Berberine
Berberine has been used to treat gastrointestinal disorders for a long time. Recent studies found
it could protect gastrointestinal tract from injure, and was effective to multiply gastrointestinal
diseases, such as ulcerative colitis. Firstly, it could ameliorate gastrointestinal inflammation. In
ethanol-induced gastric ulcer mice model, it could significantly protect ethanol-induced gastric mucosa
damage, probably by increasing the expression of eNOS while inhibiting the expression of iNOS (Pan
et al., 2005). In lipopolysaccharides (LPS)-induced rat and mouse intestinal injury, it could inhibit
intestinal inflammation, such as inhibition of COX-2 expreesion, enterocyte apoptosis, neutrophil
infiltration, and therefore alleviate intestinal damage, probably through increasing the activities SOD
and glutathione peroxidase (GSH-Px), inhibiting TLR4-NF-κB and p38-PPAR-γ signaling pathways
(Feng et al., 2011; Li et al., 2011; Zhang et al., 2011). In 2,4,6-trinitrobenzene sulfonic acid (TNBS)-
induced mice colitis, it could improve colitis via inhibiting lipid peroxidation, enterobacterial growth
and NF-κB activation (Lee et al., 2010). In indomethacin (IND)-induced mouse small intestinal injure,
it could prevent IND-induced enteropathy and reduce the incidence of mice lethality by decreasing the
elevation of adenosine via inhibiting adenosine deaminase (ADA), a key enzyme of adenosine
catabolism (Watanabe-Fukuda et al., 2009). Secondly, it could inhibit intestinal epithelial barrier
damage. In vitro model of intestinal epithelial cell (Caco-2) monolayers, it could increase tight
junction integrity by measuring transepithelial electrical resistance (TEER), and attenuate TNF-α and
IFN-γ-induced barrier penetration via inhibiting the dislocation of tight junction protein occludin from
raft fractions to non-raft fractions in membrane microdomains (Gu et al., 2009; Ning et al., 2010). It
could also antagonize TNF-α-mediated barrier defects in HT-29/B6 human colon monolayers and rat
colon, through preventing TNF-α-induced claudin-1 disassembly and upregulation of claudin-2
(Amasheh et al., 2010). In a mouse model of endotoxinemia, it could attenuate the disruption of tight
junctions in intestinal epithelium, probably mediated by inhibiting NF-κB and myosin light chain
kinase pathway (Gu et al., 2011). In addition, berberine could inhibit radiation-induced intestinal
injure. In mice undergoing abdominal radiotherapy, it could attenuate mice intestinal injury and delay
mice mortality (Li et al., 2010). In a small clinical trial, it could significantly decrease the incidence
and severity of radiation-induced acute intestinal symptoms (RIAISs), and postpone the occurrence of
RIAIS in patients with abdominal or whole pelvic radiation (Li et al., 2010).
5. 10. Anti-rheumatic Effect of Berberine
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63
Rheumatic diseases, such as rheumatoid arthritis (RA) and osteoarthritis, are a series of
inflammatory disorders mainly affecting joints and connective tissue. Berberine was found to be
effective to rheumatic diseases due to its important bioactive abilities, such as anti-inflammatory
ability. It was reported to ameliorate rheumatic arthritis. Activated rheumatoid arthritis fibroblast-like
synoviocytes (RAFLSs) play a vital role in the initiation and progression of RA, and berberine could
inhibit RAFLS proliferation and increasing RAFLS apoptosis, probably through induction of cell cycle
arrest at the G0/G1 phase and regulation of apoptosis mediators, respectively (Wang et al., 2011). It
could also alleviate osteoarthritis. In rabbit articular chondrocytes and experimental rat osteoarthritis
model, it could inhibit IL-1β-induced release of collagen, proteoglycan, glycosaminoglycan (GAG)
and NO, as well as down-regulate MMPs and up-regulate tissue inhibitor of metalloproteinase (TIMP-
1) (Hu et al., 2011; Moon et al., 2011). In osteoblastic cells, it could promote osteoblast differentiation
by Runx2 activation through p38 MAPK signaling pathway (Lee et al., 2008). Meanwhile, it could
inhibit osteoclast formation and survival via suppression of NF-κB and Akt activation (Hu et al.,
2008). In glucocorticoid-induced osteoporosis rats, it could inhibit bone resorption while improve bone
formation (Xu et al., 2010). Therefore, it may have a therapeutic potential for the treatment of cartilage
damage in osteoarthritis.
5.11. Other Bioactivities of Berberine
Except what discussed above, berberine has many other bioactivities and pharmacological
effects (Table 2), such as anti-angiogenic and anti-clastogenic effects.
Table 2. Other Bioactivities of Berberine
Bioactivites Mechanisms References
Anti-angiogenic effect Inhibition of HIF, VEGF, MMP2, and
pro-inflammatory factors
Gao et al., 2009; Hamsa and
Kuttan, 2012; Jie et al., 2011
Anti-clastogenic effect Inhibition of lipid peroxidation and
modulation of phase I and II
detoxification cascade.
Sindhu and Manoharan, 2010
Anti-convulsant effect Modulation of neurotransmitter
systems
Bhutada et al., 2010
Anti-depressant effect Modulation of brain biogenic amines
via NO-cGMP signaling pathway
Kulkarni and Dhir, 2007 & 2008;
Peng et al., 2007
Anti-diarrhea effect Reduction of epithelial gut
permeability
Gu et al., 2009
Anti-skin aging effect Prevention of skin inflammation and
the degradation of extracellular matrix
proteins
Kim and Chung, 2008; Kim et al.,
2008
Anti-uveitis effect Inhibition of inflammatory mediators,
such as MCP-1, CINC-1 and IL-8
Cui et al., 2006 & 2007
Muscle-relaxing effect Inhibition of muscarinic acetylcholine
receptors
Sanchez-Mendoza et al., 2008
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64
cGMP: cyclic guanosine monophosphate; CINC-1: cytokine- induced neutrophil chemoattractant-1;
HIF: hypoxia-inducible factor; IL-8: interleukin-8; MCP-1: monocyte chemotactic protein 1; MMP2:
matrix metalloproteinase 2; VEGF: vascular endothelial growth factor.
6. Conclusions and Prospects
Although berberine-containing medicinal plants have been used for a long time in traditional
medicines, berberine has just attracted increasing research interest in recent years due to its various
significant bioactivities. This review mainly summarized recent studies on its natural sources,
separation and detection methods, absorption and metabolism, as well as bioactivities, which were
specially emphasized. However, most studies on its beneficial effects were based on cell and animal
disease models, the effects of berberine on human diseases remain largely uncertain. Therefore, in the
future, clinical trials are appreciated to verify the beneficial effects of berberine on human. Besides,
this already accumulated evidence can also provide important theoretical basis for its clinical
application in the future.
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